Project Abstract Prostate cancer is one of the leading cancers in the U.S. population and the second leading cause of cancer death in men. Accurate prostate imaging could significantly improve accuracy of the prostate cancer diagnoses and disease progression assessments. Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein that is abundantly expressed on the surface of prostate cancer cells. There are up to 1 million PSMA proteins per cell, making it an excellent target for imaging of prostate cancer. Our group has successfully developed a series of PSMA-based novel low molecular weight PET and SPECT agents for prostate cancer radionuclide imaging. Recently, we reported low molecular weight PSMA-based fluorescent imaging agents derived from conjugation of optical dyes with PSMA-binding ligand and those compounds have shown specific PSMA+ tumor uptake in mice. Optical imaging is very sensitive and can provide high contrast for tumor versus normal cells. However, it has limited penetration depth due to the scattering of the light. Photoacoustic (PA) imaging, based on the photoacoustic effect, is a noninvasive and nonionizing hybrid imaging modality that combines the high contrast of optical contrast with high spatial resolution of ultrasound imaging. It is a promising new biomedical imaging technique with great potential for clinic imaging applications. In this proposal, we are going to design, synthesize and evaluate novel PSMA-targeted low molecular weight PA imaging contrast agents for photoacoustic imaging of prostate cancer. As with our radiotracers and other optical agents, these new agents are expected to concentrate selectively within PSMA-expressing tumors, thereby enhancing the targeting specificity of the PA imaging. The ultimate goal of this project is to developing a new prostate cancer imaging method for improve the prostate cancer diagnosis and treatment monitoring.